The present invention relates to alkynyl amides, to the use of these compounds to treat seizures, migraine, and psychiatric disorders, and to the preparation of these compounds.
Epilepsy affects roughly 1% of the world""s population. Among the drugs employed for control of epileptic seizures is valproic acid. Valproic acid (also referred to as VPA, valproate, di-n-propylacetic acid, DPA, 2-propylvaleric acid or 2-propylpentanoic acid) is an effective anticonvulsant.
Migraine is defined as a periodically occurring vascular headache characterized by pain in the head (usually unilateral), nausea and vomiting, photophobia, phonophobia, vertigo and general weakness. Migraine is the most common type of vascular headache and affects as much as 15% of the world""s population. Of the different types of migraines, classical migraine and common migraine are the two most prevalent. The major difference between the two types of migraines is that classical migraines are preceded by the appearance of neurological symptoms before an attack whereas common migraines are not preceded by such symptoms. Migraine is caused by intermittent brain dysfunction. However, the precise pathophysiological mechanisms involved are not understood. The head pain is believed to involve blood vessel dilation.
Analgesics are often used to treat infrequent and mild migraines. Analgesics reduce the pain of a migraine and, in the case of aspirin, also discourage platelet aggregation. However, for moderate to severe migraines, stronger medications such as ergotamine and valproic acid are often necessary. Ergotamine tartrate is a vasoconstrictor which counteracts the painful dilation stage of the headache. When taken during the early stages of an attack, ergotamine tartrate helps to relieve the classic and common migraine symptoms. Valproic acid has been shown to be effective in prevention of migraine, however, its mechanism of anti-migraine action is unclear. It is believed that valproic acid increases brain gamma-aminobutyric acid (GABA) levels and in doing so may activate the GABA receptor and suppresses migraine-related events.
A number of psychiatric disorders may be treated with valproic acid, see: Loscher W., ed. Valproate, Basel Switzerland: Birkhauser Verlag, 1999; Post R. M., In Tasman A., Goldfinger, S. M., Kaufmann, C. A., eds. Review of psychiatry, volume 9, Washington D.C.: American Psychiatric Press, 1990, 170-202; and Jensen R., Brinck T., Olesen J., Neurology 44, 1994, 647. Such psychiatric disorders include: i) Mood Disorders; ii) Anxiety Disorders; iii) Attention-Deficit and Disruptive Behavior Disorders; iv) Behavioral Disturbances associated with dementia; v) Behavioral Disturbances associated with autism; vi) Schizophrenia; vii) Impulse Control Disorders; viii) Personality Disorders; and ix) Substance-related Disorders.
Mood Disorders include, but are not limited to, Depressive Disorders and Bipolar Disorders such as Manic episodes and Mixed episodes. Symptoms associated with Mood Disorders include, but are not limited to, depression, elevated, expansive or irritable mood, insomnia/hypersomnia, agitation and distractability or impulsivity.
Anxiety Disorders include, but are not limited to, Panic Disorder, Posttraumatic Stress Disorder and Generalized Anxiety Disorder. Symptoms associated with Anxiety Disorders include, but are not limited to, anxious mood, panic attacks, irritability, outbursts of anger and exaggerated startle response.
Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, Attention-Deficit/Hyperactivity Disorder Hyperactive-Impulsive Type, Conduct Disorder, Oppositional Defiant Disorder and Disruptive Behavior Disorder. Symptoms associated with Attention-Deficit and Disruptive Behavior Disorders include, but are not limited to, impulsivity, aggression, anger and loss of temper.
Symptoms associated with Behavioral Disturbances for both dementia and autism include, but are not limited to, verbal and physical agitation and aggression.
Symptoms associated with Substance-related Disorders, include but are not limited to, withdrawal and dependence.
Symptoms associated with schizophrenia, include but are not limited to, positive symptoms, negative symptoms and agitation.
Impulse Control Disorders include, but are not limited to, Intermittent Explosive Disorder. Symptoms associated with Impulse Control Disorders, include but are not limited to, verbal or physical aggressive impulses.
Personality Disorders include, but are not limited to, Borderline Personality Disorder. Symptoms associated with Personality Disorders, include but are not limited to, mood lability, irritability, agitation and aggression.
The symptoms listed for these psychiatric disorders are not an exhaustive description of the diagnostic category or disorder, but merely reflect some of the symptoms that may improve when treated with valproic acid. For Example, valproic acid may be used to treat general agitation or aggression not necessarily associated with any particular psychiatric-disorder.
Further, excitatory neurotransmitters such as glutamate and aspartate, as well as a variety of voltage-gated ion channels, are thought to play a central role in mediating cell death after a variety of cerebral insults including, but not limited to, ischemia, trauma, seizure and hypoglycemia. Many studies have shown that compounds or therapeutic strategies that decrease excitatory neurotransmission, for example, glutamate antagonists, ion channel blockers, anticonvulsants, and the like, elicit a neuroprotective effect in animal models of cerebral insults.
Recently, VPA has been shown to increase the levels of the neuroprotective protein B cell lymphoma protein-2 (bcl-2) in frontal cortex, findings that may have implications for the long-term treatment of various neurodegenerative disorders (Chen G., et al, Journal of Neurochemistry, 1999, 879-882).
Neuropathic pain affects a significant number of patients suffering from disorders of the brain or spinal cord, such as stroke, trauma, multiple sclerosis, and diabetes. Several known anticonvulsant compounds are efficacious in various analgesia models relevant to identifying therapeutic candidates for treating neuropathic pain (Lloyd and Morselli, in Psychopharmacology: The Third Generation of Progress, Raven Press, 1987). The use of anticonvulsants like valproate to treat various pain states has been documented extensively (Swendlow, J. Clin. Neuropharmacol., 7, 1984, 51-82).
Restlessness syndrome denotes a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as well as by a sense of physical (rather than mental) agitation, which is independent of mood and, hence, is distinguished from restlessness per se, see (Sachdev et al., Austral. New Zealand J. Psychiatry 30, 1996, 38-53.
The genus of restlessness syndromes, inclusive of numerous indications, can be observed in association with many organic and non-organic psychiatric illnesses. For example, drug-induced restlessness (tardive, chronic, and withdrawal akathisias), such as drug-induced extrapyramidal symptoms, is one of the most common side effects of neuroleptic, drug therapy. Also within the restlessness syndrome rubric are the so-called xe2x80x9crestless leg syndromexe2x80x9d and xe2x80x9csleep-related periodic leg movements,xe2x80x9d pathologies that can be associated with head and/or spinal cord trauma and with lesions of the spinal cord. Idiopathic restless leg syndrome follows an autosomal dominant inheritance, with a variable clinical expression of symptoms.
Diminished GABAergic neurotransmission is implicated in the neurochemical basis of restlessness syndromes. Consistent with this notion, for instance, is the efficacy of drugs such as baclofen, valproate, gabapentin and the benzodiazepines, in the treatment of restless leg syndrome, an important indication, see (O""Keefe, Arch. Intem. Med. 156, 1996, 24348; Danek et al., in Neurological Disorders: Course and Treatment, pages 819-23, Academic Press, 1996; and Mellick and Mellick, Neurology 45(suppl), 1995, 285-86).
A relationship has been reported between epilepsy, migraine and psychiatric disorders (Post and Silberstein, Neurology, 1994, 44(suppl 7), S37-S47). Although the three disorders are distinct, they all are paroxysmal dysregulations of the nervous system that partially overlap in their pharmacology. Some drugs, such as valproic acid, are effective in treating all three syndromes, see: (Post R. M., In Tasman A., Goldfinger, S. M., Kaufmann, C. A., eds. Review of psychiatry, volume 9, Washington D.C.: American Psychiatric Press, 1990, 170-202; and Jensen R., Brinck T., Olesen J., Neurology 44, 1994, 647), suggesting the presence of shared underlying pathophysiology, while other drugs are effective for treating one syndrome. For example, xcex2-adrenergic adrenoreceptor blockers which are effective against migraine are not useful for treating the other two syndromes and may even exasperate depression.
There has been considerable effort to discover analogs of valproic acid that are equally effective. One study has demonstrated that the valproic acid analog 2-propyl-4-hexynoic acid is an effective antiepileptic with a longer duration of activity.
Alpha-fluorinated valproic acid, 2-fluoro-2-propylpentanoic acid, has also been reported (Ph.D. thesis of Wei Tang, University of British Columbia, 1996; W. Tang et al., Chem. Res. Toxicol. (1995), 8(5), 671-682; M. Jurima-Romet et al., Toxicology (1996), 112(1), 69-85; W. Tang and F. Abbott, Drug Metab. Dispos. (1997), 25(2), 219-227). The anticonvulsant activity and pharmacokinetics of this compound were studied, and its pharmaceutical potential was speculated upon (F. Abbott, W. Tang, J. Palaty, J. Pharmacol. Exp. Ther. (1997), 282, 1163-1172). The compound was reported to be less potent than VPA, and the hepatotoxic, sedative, or teratogenic properties were not disclosed.
In its principle embodiment, the present invention discloses compounds of formula (I): 
wherein
R1 is selected from the group consisting of alkyl and haloalkyl;
R2 is selected from the group consisting of hydrogen, alkyl and fluorine;
R3 is selected from the group consisting of hydrogen, alkyl and (NRARB)carbonylalkyl wherein RA and RB are each independently selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen and alkyl; and
R5 is selected from the group consisting of hydrogen and alkyl.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
In its principle embodiment, the present invention discloses compounds of formula (I): 
wherein
R1 is selected from the group consisting of alkyl and haloalkyl;
R2 is selected from the group consisting of hydrogen, alkyl and fluorine;
R3 is selected from the group consisting of hydrogen, alkyl and (NRARB)carbonylalkyl wherein RA and RB are each independently selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen and alkyl; and
R5 is selected from the group consisting of hydrogen and alkyl.
In a preferred embodiment, compounds of the present invention have formula (I) wherein R2 is hydrogen; R1, R3, R4 and R5 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R2 is alkyl; R1, R3, R4 and R5 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R2 is fluorine; R1, R3, R4 and R5 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R5 is methyl; and R2, R3 and R4 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R3 is hydrogen; R5 is methyl; and R2 and R4 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R3 is (NRARB)carbonylalkyl; R5 is methyl; and R2 and R4 are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R2 is hydrogen; R3 is (NRARB)carbonylalkyl; R5 is methyl; and R4 is as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R2 is fluorine; R3 is (NRARB)carbonylalkyl; R5 is methyl; and R4 is as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (I) wherein R1 is propyl; R2 is alkyl; R3 is (NRARB)carbonylalkyl; R5 is methyl; and R4 is as defined in formula (I).
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
A preferred embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2R)-2-propyl-4-hexynamide in combination with a pharmaceutically acceptable carrier.
Another preferred embodiment of the present invention relates to a method of treating epilepsy, migraine or a psychiatric disorder selected from Mood Disorders, Anxiety Disorders, Attention-Deficit and Disruptive Behavior Disorders, Behavioral Disturbances associated with dementia, Substance Abuse-related Disorders, Schizophrenia, Impulse Control Disorders, Personality Disorders and Behavioral Disturbances associated with autism in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound selected from (2R)-N-(2-amino-2-oxoethyl)-2-propyl-4-hexynamide; (2R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-propyl-4-hexynamide; (2R)-N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-2-propyl-4-hexynamide; (2R)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-propyl-4-hexynamide; and (2R)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-propyl-4-hexynamide in combination with a pharmaceutically acceptable carrier.
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, heptyl, octyl, nonyl, and decyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2,2,3,3,3,-pentafluoropropyl and 2-chloro-3-fluoropentyl.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9cxe2x80x94NRARB,xe2x80x9d as used herein, refers to two groups, RA and RB, which are appended to the parent molecular moiety through a nitrogen atom. RA and RB are each independently selected from hydrogen and alkyl.
The term xe2x80x9c(NRARB)carbonyl,xe2x80x9d as used herein, refers to a xe2x80x94NRaRB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term xe2x80x9c(NRARB)carbonylalkyl,xe2x80x9d as used herein, refers to a (NRARB)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)carbonylalkyl include, but are not limited to, 2-amino-2-oxoethyl, (1S)-2-amino-1-methyl-2-oxoethyl, (1R)-2-amino-1-methyl-2-oxoethyl, (1S)-1-(aminocarbonyl)-2-methylpropyl, (1R)-1-(aminocarbonyl)-2-methylpropyl, (1S)-1-(aminocarbonyl)-3-methylbutyl, (1R)-1-(aminocarbonyl)-3-methylbutyl, and (1S,2R)4-amino-2-ethyl-1-isobutyl-4-oxobutyl.
Preferred compounds of formula (I) include,
(2R)-N-(2-amino-2-oxoethyl)-2-propyl-4-hexynamide;
(2R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-propyl-4-hexynamide;
(2R)-N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-2-propyl-4-hexynamide;
(2R)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-propyl-4-hexynamide; and
(2R)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-propyl-4-hexynamide.
A most preferred compound is (2R)-2-propyl-4-hexynamide.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; HRMS for High Resolution Mass Spectroscopy; and LDA for lithium dilsopropylamine.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-3. 
Alkynyl amides of general formula (3), wherein R1, R3, R4 and R5 are as defined in formula (I), may be prepared as described in Scheme 1. Alkynyl acids of general formula (1), prepared according to U.S. Pat. No. 5,786,380 hereby fully incorporated by reference, may be treated with oxalyl chloride and catalytic DMF in a solvent such as methylene chloride to provide crude acid chlorides. The crude acid chlorides may then be treated with an amine of general formula (2) in a solvent such as methylene chloride to provide alkynyl amides of general formula of general formula (3). 
Alkynyl amides of general formula (9), wherein R1, R3, R4 and R5 are as defined in formula (I) and R2 is alkyl, may be prepared as described in Scheme 2. Alkynyl acids of general formula (I) may be treated with HCl in methanol to provide alkynyl esters of general formula (5). Alkynyl esters of general formula (5) may be treated with lithium diisopropylamine and an alkyl halide to provide esters of general formula (6). Esters of general formula (6) may be treated with aqueous base such as potassium hydroxide in a solvent such as water/ethanol to provide acids of general formula (7). Acids of general formula (7) may be separated into individual enantiomers using chiral auxiliaries which is well known in the art such as the use of chiral oxazolidinones (Evans et al. J. Am. Chem. soc., (1982)104 1737-1739) to provide chiral acids of general formula (8). An example of separation of similar acids is described in U.S. Pat. No. 5,786,380. Chiral acids of general formula (8) may be processed as described in Scheme 1 to provide alkynyl amides of general formula (9). 
Alkynyl amides of general formula (12), wherein R1, R3, R4 and R5 are as defined in formula (1), may be prepared as described in Scheme 3. Esters of general formula (5) may be treated with lithium diisopropylamine and an electrophilic source of fluorine such as N-fluoro-N-[(trifluoromethyl)sulfonyl]trifluoromethanesulfonamide, other reagents known to be electrophilic sources of fluorine may be purchased commercially or prepared as described in (Chem. Rev., (1996) vol. 96 No.5; and Clark, J. H., Wails, D., Bastock, T. W., Aromatic Fluorination, CRC Press, 1996), to provide fluorinated ester of general formula (11). Fluorinated esters of general formula (11) may be processed as described in Scheme 2 to provide alkynyl amides of general formula (12).